The overall goal of this project is to address the need for an effective therapy for patients with severe combined immunodeficiency due to loss of CD45 function. CD45 deficiency is one of a group of genetic diseases that results in severe combined immunodeficiency (SCID). Advances in knowledge of the role of CD45 function and the demonstration of the phenotypic properties of CD45 knockout mice provided the rationale to look for CD45 aberrations in the fairly large proportion of SCID patients with unknown genetic defects. CD45 deficiency in man and knockout mouse strains results in impaired T cell development and defective T and B cell functional capabilities. The T cell developmental defects produce low levels of peripheral T cells but normal or even increased B cell numbers. Activation of B and T cells by antigen is severely diminished. In the two cases of CD45 deficiency that have been reported thus far, both patients presented at two months of age and died within two years in spite of currently available therapies. Thus, there is a need for improved therapies for this disease. We propose to develop a CD45-replacement gene therapy to correct the genetic deficiency in the patients' hematopoietic cells and thereby provide a superior treatment. The specific aims are designed the take advantage of the development of a CD45 minigene which mimics the hematopoietic expression characteristics and lineage specific expression patterns of the native gene and which also, restores immune function to CD45-null cells. Importantly, the project utilizes our considerable experience with lentiviral gene transfer vector technology. [unreadable] [unreadable]